Abstract
E-Δ2-valproic acid (E-Δ2-VPA), a major active metabolite of VPA, has been proposed as an alternative to VPA because it is less hepatotoxic and is nonteratogenic. In rodents, VPA and E-Δ2-VPA have a brain tissue/free plasma concentration ratio less than unity, which suggests rapid removal of the alkanoate anticonvulsants from the central nervous system. This study in rabbits employed a simultaneous iv infusion-ventriculocisternal (VC) perfusion technique to investigate the steady-state kinetics of E-Δ2-VPA transport at the blood-brain barrier, the blood-cerebrospinal fluid (CSF) barrier, and the neural cell membrane. Probenecid (PBD) was coadministered to probe the mediation of transport by organic anion transporter(s). Rabbits in the control group (N = 6) received an iv infusion of E-Δ2-VPA to achieve a steady-state plasma concentration of 50 to 60 μg/ml. Blood and cisternal outflow of mock CSF perfusate were continuously sampled. Midway through the experiment, the VC perfusate was switched to one containing [3H]E-Δ2-VPA. At 225 min, the rabbits were sacrificed, and each brain was removed and dissected into ten regions. Rabbits in the PBD group (N = 9) received an iv infusion and VC perfusion as in the control group as well as concomitant iv infusion of the inhibitor. The mean steady-state VC extraction ratio for [3H]E-Δ2-VPA did not differ between the control and PBD groups (63.7 ± 8.3%vs. 60.6 ± 9.6%), indicating the lack of a significant PBD-sensitive transport at the choroidal epithelium. Coadministration of PBD elevated brain concentration of cold E-Δ2-VPA in the absence of a significant change in total or free steady-state plasma concentration. Mean E-Δ2-VPA brain tissue/free plasma concentration ratios in the various brain regions were 3.5- to 5.2-fold higher in PBD-treated animals than in the controls. Significant increases (3.0- to 4.5-fold) in the mean brain tissue/cisternal perfusate concentration ratios were also observed. Compartmental modeling of the steady-state distribution data suggested that clearance of E-Δ2-VPA from the brain parenchyma is governed jointly by efflux transporters at the neural cell membrane and brain capillary endothelium. Moreover, PBD-induced elevation of E-Δ2-VPA tissue concentrations is attributed primarily to inhibition of E–Δ2-VPA efflux transport at the neural cell membrane, resulting in both intracellular trapping and greater tissue retention of E–Δ2-VPA.
Footnotes
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Send reprint requests to: Danny D. Shen, Ph.D., Department of Pharmaceutics, Box 357610, University of Washington, Seattle, WA 98195-7610.
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This research was supported by National Institutes of Health Grant NS-30738.
- Abbreviations used are::
- VPA
- valproic acid
- CSF
- cerebrospinal fluid
- CNS
- central nervous system
- VC
- ventriculocisternal
- PBD
- probenecid
- BBB
- blood-brain barrier
- Received February 25, 1997.
- Accepted September 8, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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